NM_003392.7:c.141-8C>A

Variant names:

• chr3-55479572-G-T
• rs188798140
• NM_003392.7:c.141-8C>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_003392.7(WNT5A):​c.141-8C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000287 in 1,569,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: WNT5A NM_003392.7 splice_region, intron
• Scores: Splicing: ADA: 0.002246
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.335
• Publications: 0 publications found

Genes affected

WNT5A (HGNC:12784): (Wnt family member 5A) The WNT gene family consists of structurally related genes which encode secreted signaling proteins. These proteins have been implicated in oncogenesis and in several developmental processes, including regulation of cell fate and patterning during embryogenesis. This gene encodes a member of the WNT family that signals through both the canonical and non-canonical WNT pathways. This protein is a ligand for the seven transmembrane receptor frizzled-5 and the tyrosine kinase orphan receptor 2. This protein plays an essential role in regulating developmental pathways during embryogenesis. This protein may also play a role in oncogenesis. Mutations in this gene are the cause of autosomal dominant Robinow syndrome. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2012]

WNT5A Gene-Disease associations (from GenCC):

• autosomal dominant Robinow syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• autosomal dominant Robinow syndrome

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 3-55479572-G-T is Benign according to our data. Variant chr3-55479572-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1571175.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 42 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003392.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WNT5A	NM_003392.7	MANE Select	c.141-8C>A		splice_region intron	N/A	NP_003383.4
	WNT5A	NM_001256105.1		c.96-8C>A		splice_region intron	N/A	NP_001243034.1
	WNT5A	NM_001377271.1		c.96-8C>A		splice_region intron	N/A	NP_001364200.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WNT5A	ENST00000264634.9	TSL:1 MANE Select	c.141-8C>A		splice_region intron	N/A	ENSP00000264634.4
	WNT5A	ENST00000474267.5	TSL:5	c.141-8C>A		splice_region intron	N/A	ENSP00000417310.1
	WNT5A	ENST00000497027.5	TSL:2	c.96-8C>A		splice_region intron	N/A	ENSP00000420104.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000694 AC: 16 AN: 230506 AF XY: 0.0000880

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000653

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000582

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000659

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000296 AC: 42 AN: 1417600 Hom.: 0 Cov.: 30 AF XY: 0.0000272 AC XY: 19 AN XY: 699200

African (AFR) AF: 0.0000310 AC: 1 AN: 32266

American (AMR) AF: 0.000146 AC: 6 AN: 41176

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24676

East Asian (EAS) AF: 0.00 AC: 0 AN: 38838

South Asian (SAS) AF: 0.000101 AC: 8 AN: 79356

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52536

Middle Eastern (MID) AF: 0.000538 AC: 3 AN: 5580

European-Non Finnish (NFE) AF: 0.0000157 AC: 17 AN: 1084812

Other (OTH) AF: 0.000103 AC: 6 AN: 58360

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152148 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74320

African (AFR) AF: 0.0000241 AC: 1 AN: 41434

American (AMR) AF: 0.0000655 AC: 1 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	WNT5A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	13
DANN	Benign	0.61
PhyloP100		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0022
dbscSNV1_RF	Benign	0.12
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs188798140; hg19: chr3-55513600;